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<p>As a novel therapeutic strategy, targeted protein degradation (TPD) enables the selective elimination of disease-driving proteins through endogenous degradation pathways such as the ubiquitin-proteasome system and lysosomal trafficking. However, the therapeutic potential of TPD agents is often limited by poor solubility, low bioavailability, off-target toxicity, and inefficient intracellular delivery. Nanocarrier-based delivery systems offer a promising solution to these challenges by enabling controlled release, enhanced pharmacokinetics, and precise intracellular trafficking of TPD agents, including PROteolysis TArgeting Chimera (PROTACs), LYsosome-TArgeting Chimeras (LYTACs), or AUtophagy-TArgeting Chimeras (AUTACs). These systems can be engineered to respond to tumor-specific internal stimuli (e.g., pH, redox environment, enzymes) or external triggers (e.g., light, ultrasound, magnetic fields), enabling spatiotemporal control of drug release while minimizing systemic toxicity. Furthermore, modular nanocarrier designs allow for co-delivery with synergistic therapeutics, improved endosomal escape, and surface modification for cell-specific targeting. Recent innovations, including the development of exosome-based and carrier-free nanotechnology-enabled TPD platforms (Nano-TPDs), further expand the landscape of degradable targets and therapeutic indications. This review highlights the design principles, current advances, and future directions of nano-TPD systems, with an emphasis on their potential to overcome delivery barriers and redefine precision oncology.</p><p></p>

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Nano-TPD: Using nanoparticle-based systems to improve the delivery and therapeutic effect of targeted protein degraders

  • 期刊论文

  • 发表日期：

    2025年8月19日

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  • Kuntala Dey,
  • Nina Erwin,
  • Nicolas Molina,
  • Hui Chen,
  • Mei He,
  • Guangrong Zheng

摘要

As a novel therapeutic strategy, targeted protein degradation (TPD) enables the selective elimination of disease-driving proteins through endogenous degradation pathways such as the ubiquitin-proteasome system and lysosomal trafficking. However, the therapeutic potential of TPD agents is often limited by poor solubility, low bioavailability, off-target toxicity, and inefficient intracellular delivery. Nanocarrier-based delivery systems offer a promising solution to these challenges by enabling controlled release, enhanced pharmacokinetics, and precise intracellular trafficking of TPD agents, including PROteolysis TArgeting Chimera (PROTACs), LYsosome-TArgeting Chimeras (LYTACs), or AUtophagy-TArgeting Chimeras (AUTACs). These systems can be engineered to respond to tumor-specific internal stimuli (e.g., pH, redox environment, enzymes) or external triggers (e.g., light, ultrasound, magnetic fields), enabling spatiotemporal control of drug release while minimizing systemic toxicity. Furthermore, modular nanocarrier designs allow for co-delivery with synergistic therapeutics, improved endosomal escape, and surface modification for cell-specific targeting. Recent innovations, including the development of exosome-based and carrier-free nanotechnology-enabled TPD platforms (Nano-TPDs), further expand the landscape of degradable targets and therapeutic indications. This review highlights the design principles, current advances, and future directions of nano-TPD systems, with an emphasis on their potential to overcome delivery barriers and redefine precision oncology.